Feature Articles

Biomarkers Inform Cancer Research

Deciphering Diabetes

HbA1, a broad measure of glucose control, remains the dominant marker used in diabetes despite the disease’s substantial heterogeneity.

“We have a glucose centric picture for type 2 diabetes (T2D),” said Mark Broenstrup, Ph.D., director, biomarkers and diagnostics, diabetes, Sanofi. “We believe this picture is too simplistic and would like to dissect T2D into subtypes that better capture the pathophysiological effects in the individual.”

So far that has proven difficult to do even though diabetes’ many complications (blindness, nephropathy, heart disease, neuropathy, etc.) can be devastating. “We have a good understanding of individual mechanism, but understanding the interplay between mechanisms will require a systems biology view,” said Dr. Broenstrup.

Currently, roughly nine classes of drugs target diabetes. “It’s a challenge to position new drug classes if we only have glucose lowering information; the payers will tell us we have other principles that are generic and cheaper than your new one that also lower glucose. Why should we take yours?”

To manage costs Sanofi is leveraging public-private partnerships such as the European Medicine Initiative, which has three diabetes-related projects, each with a strong biomarker component. “We are leading IMIDIA, a program on beta cells, and DIRECT, a personalized medicine diabetes effort,” said Dr. Broenstrup.

Progress is being made on markers for progression to T2D, said Dr. Broenstrup. New reagents are enabling beta cell imaging (beta cell mass is used as measure of insulin-producing capacity of the pancreas). A few liver proteins also show promise as markers. An interesting one has emerged from GWAS studies and indicates most risk signs are in beta cells and not other affected organs.

Monitoring Autoimmune Responses

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According to Life Technologies, ProtoPlex is similar to an ELISA but it uses Luminex xMAP technology, for high-throughput characterization of promising markers.

Identifying the antigens that elicit an autoimmune response can yield panels of biomarkers used to classify disease, predict patient outcomes, and characterize leads. Researchers from Life Technologies presented data from studies with the firm’s high-content ProtoArray and new ProtoPlex platforms demonstrating assay robustness and offering study design tips.

Niro Ramachandran, Ph.D., R&D manager, discussed work with protein microarrays composed of up to 9,000 purified full-length human proteins to evaluate immunological profiles across panels of serum samples. The goal was to identify biomarkers for SLE diagnosis, mesothelioma, and early detection of colorectal cancer.

Instead of printing antibodies on the slide as is often done, ProtoArray entails printing functional proteins, such as transcriptional factors, on the glass.

“It’s fundamentally a discovery tool designed to screen one-third of the proteome,” said Dr. Ramachandran.

The first coarse screening is done with ProtoArray followed by ProtoPlex, using Luminex xMAP technology, for high-throughput characterization of promising makers.

“ProtoPlex is similar to an ELISA technology except with ELISA you can test just one reaction in a well, i.e., one antigen or antibody. Luminex offers these color-coded beads that you can put different antigens on and the color can be read so it’s addressable.

“We can take 50 of these different beads and 50 different proteins and put them all in the same well and from one well you can pass serum against 50 antigens,” said Dr. Ramachandran, adding the concordance between the two platforms is around 70%, higher than mass spec.

Companies also use the platform to screen small molecules seeking protein binding information to help reveal mechanisms of action and identify leads and targets.

MSIA Platform

Roughly one year ago Thermo Scientific acquired Intrinsic Bioprobes, developer of a tip technology for purifying microscale amounts of protein or peptide antigen in complex biological fluid for subsequent mass spec. Now, Thermo is launching a set of products that comprise a complete mass spectrometric immunoassay (MSIA) platform and workflow that begins with sample prep and ends with mass spec detection.

Thermo’s tip immuno-affinity protein purification system works with Thermo’s TSQ Vantage mass spec to deliver protein and peptide quantification. A new liquid handler, Versette Pipetting Workstation, is also being launched.

Currently the platform is only for research although Thermo expects it will eventually be used as an IVT. The platform is Clinical and Laboratory Standards Institute compliant.

“We’ve been translating the tip technology into a more robust, better performing product combined with a liquid-handling systems,” said Urban Kiernan, Ph.D., senior scientist at Thermo.

“We have a couple of liquid-handling systems depending upon the amount of throughput users require.”

MSIA, say advocates, is a simpler way to generate accurate high-content data than competing technologies. Dr. Kiernan also expects the system to be used by companies needing to more accurately characterize their molecules such as in biosimilar development or by original biologics innovators seeking to differentiate their products from potential biosimilars.

“We’ve also been working with clients who use our technology to enrich proteins either from plasma or serum or even intracellular approach in which they are looking for post translational modifications that would essentially be a turn-on turn-off for a particular pathway,” he explained.

Breast Cancer Analysis Identifies Spectrum of Mutations

A major breast cancer analysis project has catalogued the spectrum of mutations that underpin the four basic categories of the disease. The data, published in Nature, represents the most comprehensive molecular blueprint of breast cancer generated to date, and could help researchers design and develop more effective drugs and combination treatment regimens that target each subtype of disease according to its molecular background.

Her2-enriched—About 7% to 12% of breast cancers. Typically, ER- and PR-, but also Her2+. These tumors have a fairly poor prognosis and are prone to early and frequent recurrence and metastases. Women with Her2+ tumors appear to be diagnosed at a younger age.

Luminal A—About 40% of all breast cancers. Low or moderate tumor grade, hence they carry the best prognosis of all breast cancer subtypes. Usually are ER+ and/or PR+, but also Her2 negative.

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